Malaria is a major public health problem in tropical regions worldwide. It is estimated that 500 million people are infected with malarial parasites annually and the problem has been exacerbated in the past 20 years by the emergence of drug resistant parasites. There is an urgent need for novel classes of antimalarial drugs. To date no malaria vaccine has been developed and parasites resistant to all classes of antimalarials exist in many areas of the world. Rational treatment policies that combine multiple classes of antimalarial drugs are being used to limit the origin and spread of drug resistance, but unfortunately there are insufficient drug classes available to ensure the long term success of this approach. The goal of this project is to isolate new chemical compounds with potent activity against drug sensitive and drug resistant malarial parasites. Compounds isolated from plants have proven to be the mainstay in antimalarial therapy for centuries. Three major drug classes in use against malaria are based on plant-derived structures. Quinine was originally isolated from Cinchona spp. and provided the chemical template for chloroquine and newer derivatives. Artemisinin was originally isolated from Artemisia annua and the newest class of compounds represented by atovaquone is structurally derived from lapachol, isolated from Tabebuia sp. There remains a good expectation that new antimalarial compounds can be identified from plants. In preliminary studies we screened a unique extract library derived from plants that thrive in the harsh environment of South Texas. Four crude extracts showed potent activity against the malaria parasite P. falciparum with an IC50 range of 1.8 - 12.2 <g/ml. Furthermore, these extracts were inactive against four mammalian cell lines at 20 5g/ml, suggesting a good selectivity index. This R21 proposal aims to isolate, identify and further characterize the active components of these four validated plant extracts and an additional 10 extracts that will be selected from secondary screening of 46 additional crude extracts with antimalarial activities. We will procure and extract the plant material and the extracts will be fractionated and the active constituents identified by bioassay-guided fractionation. The structures of the malarial-active compounds will be determined using nuclear magnetic resonance (NMR) and mass spectroscopy (MS). The active constituents will be assayed for activity against drug sensitive and drug resistant malaria parasites and human cells. Compounds that show promise for antimalarial development, defined as potent and effective against both drug sensitive and drug resistant malaria strains and a high selectivity index, will be prioritized for drug development. We are well positioned to coordinate efforts needed to move these compounds into clinical development.